Current therapy for multiple Myeloma (MM) remains unsatisfactory, and despite recent improvements in treatment, the disease remains incurable indicating the need for continued investigation of novel agents. We have investigated a novel agent, ENMD-2076, in MM. ENMD-2076 is an orally bioavailable, multi-target kinase inhibitor with a complex mechanism of action, including antiproliferative and pro-apoptotic activity, and inhibition of angiogenesis. In preclinical studies, we have shown that ENMD-2076 has significant in vitro and in vivo activity against MM cell lines and primary MM cells, and targets multiple pathways critical to the growth and survival of myeloma cells. In addition to being cytotoxic to MM cells, we have shown that ENMD-2076 cleaves Mcl-1 and down regulates the anti-apoptotic proteins survivin and X-linked inhibitor of apoptosis (XIAP);inhibits the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, fibroblast growth factor receptor-3 (FGFR3) receptor tyrosine kinase activity, and the aurora kinases A and B, inducing cycle arrest in the G2/M phase cell;and inhibits of angiogenesis. The significant activity against MM cells, and the importance of the pathways targeted by this agent in the pathogenesis of MM, provides strong rationale for clinical development of ENMD- 2076 in MM. No clinical experience has been reported with ENMD-2076. Therefore, based on our laboratory studies we propose to initiate clinical investigation of ENMD-2076 in patients with MM. Specifically, we propose 1) to conduct a phase I trial to investigate the dose limiting toxicity and maximal tolerated dose of oral ENMD-2076 in patients with relapsed or refractory MM, 2) Describe the pharmacokinetic profile of ENMD-2076 following oral administration, and 3) Assess the in vivo biological activity of ENMD-2076 on important target pathways identified in our preclinical studies, and explore the feasibility of utilizing some of these as potential biomarkers for testing in future clinical trials that will assess efficacy. The results of this research will be important to the understanding of clinical mechanism of action of ENMD-2076 and its optimal use in future clinical investigation in MM, which has important significance for the outcome of this currently incurable disease.